tbuckley/cabot-search huggingface dataset:
Multiplex epigenome editing of <i>MECP2</i> to rescue Rett syndrome neurons
Authors: Junming Qian, Xiaonan Guan, Bing Xie, Chuanyun Xu, Jacqueline Niu, Xin Tang, Charles H. Li, Henry M. Colecraft, Rudolf Jaenisch, X. Shawn Liu
Journal: Science Translational Medicine (2023)

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by loss-of-function heterozygous mutations of methyl CpG-binding protein 2 ( MECP2 ) on the X chromosome in young females. Reactivation of the silent wild-type MECP2 allele from the inactive X chromosome (Xi) represents a promising therapeutic opportunity for female patients with RTT. Here, we applied a multiplex epigenome editing approach to reactivate MECP2 from Xi in RTT human embryonic stem cells (hESCs) and derived neurons. Demethylation of the MECP2 promoter by dCas9-Tet1 with target single-guide RNA reactivated MECP2 from Xi in RTT hESCs without detectable off-target effects at the transcriptional level. Neurons derived from methylation-edited RTT hESCs maintained MECP2 reactivation and reversed the smaller soma size and electrophysiological abnormalities, two hallmarks of RTT. In RTT neurons, insulation of the methylation-edited MECP2 locus by dCpf1-CTCF (a catalytically dead Cpf1 fused with CCCTC-binding factor) with target CRISPR RNA enhanced MECP2 reactivation and rescued RTT-related neuronal defects, providing a proof-of-concept study for epigenome editing to treat RTT and potentially other dominant X-linked diseases.
Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models
Authors: Katharina M. Eyme, Alessandro Sammarco, Roshani Jha, Hayk Mnatsakanyan, Caline Pechdimaljian, Litia Carvalho, Rudolph Neustadt, Charlotte Moses, Ahmad Alnasser, Daniel F. Tardiff, Baolong Su, Kevin J. Williams, Steven J. Bensinger, Chee Yeun Chung, Christian E. Badr
Journal: Science Translational Medicine (2023)

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.
The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson’s disease
Authors: Senthilkumar S. Karuppagounder, Hu Wang, Terence Kelly, Roger Rush, Richard Nguyen, Shivani Bisen, Yoko Yamashita, Nicholas Sloan, Brianna Dang, Alexander Sigmon, Hyeun Woo Lee, Shirley Marino Lee, Leslie Watkins, Erica Kim, Saurav Brahmachari, Manoj Kumar, Milton H. Werner, Ted M. Dawson, Valina L. Dawson
Journal: Science Translational Medicine (2023)

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein–dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.
Aging alters the cell cycle control and mitogenic signaling responses of human hematopoietic stem cells
Authors: Colin A. Hammond, Si Wei Wu, Fangwu Wang, Margarita E. MacAldaz, Connie J. Eaves
Journal: Blood (2023)

Human hematopoietic stem cells (HSCs), like their counterparts in mice, comprise a functionally and molecularly heterogeneous population of cells throughout life that collectively maintain required outputs of mature blood cells under homeostatic conditions. In both species, an early developmental change in the HSC population involves a postnatal switch from a state in which most of these cells exist in a rapidly cycling state and maintain a high self-renewal potential to a state in which the majority of cells are in a quiescent state with an overall reduced self-renewal potential. However, despite the well-established growth factor dependence of HSC proliferation, whether and how this mechanism of HSC regulation might be affected by aging has remained poorly understood. To address this knowledge gap, we isolated highly HSC-enriched CD34+CD38-CD45RA-CD90+CD49f+ (CD49f+) cells from cord blood, adult bone marrow, and mobilized peripheral blood samples obtained from normal humans spanning 7 decades of age and then measured their functional and molecular responses to growth factor stimulation in vitro and their regenerative activity in vivo in mice that had undergone transplantation. Initial experiments revealed that advancing donor age was accompanied by a significant and progressively delayed proliferative response but not the altered mature cell outputs seen in normal older individuals. Importantly, subsequent dose-response analyses revealed an age-associated reduction in the growth factor-stimulated proliferation of CD49f+ cells mediated by reduced activation of AKT and altered cell cycle entry and progression. These findings identify a new intrinsic, pervasive, and progressive aging-related alteration in the biological and signaling mechanisms required to drive the proliferation of very primitive, normal human hematopoietic cells.
Disparities According to Genetic Ancestry in the Use of Precision Oncology Assays
Authors: Douglas A Mata, Lisa S Rotenstein, Marco A Ramos, Anupam B Jena
Journal: New England Journal of Medicine (2023)

concentrations in plasma (Table S4).The highest plasma concentration of tecovirimat after one dose was 200 to 1000 times as high as the IC 50 values for the agent.The plasma concentrations of brincidofovir were 3.9 to 67.0 times as high as the IC 50 values, and the plasma concentrations of cidofovir were 2.5 to 16.0 times as high as the IC 50 values.Our data indicate that the currently circulating MPXVs are likely to remain sensitive to the available antiviral drugs.
Use of Wastewater for Mpox Outbreak Surveillance in California
Authors: Marlene K Wolfe, Alexander T Yu, Dorothea Duong, Madhura S Rane, Bridgette Hughes, Vikram Chan-Herur, Marisa Donnelly, Shua Chai, Bradley J White, Duc J Vugia, Alexandria B Boehm
Journal: New England Journal of Medicine (2023)
Protection against Reinfection with the Omicron BA.2.75 Subvariant
Authors: Hiam Chemaitelly, Patrick Tang, Peter Coyle, Hadi M Yassine, Hebah A Al-Khatib, Maria K Smatti, Mohammad R Hasan, Houssein H Ayoub, Heba N Altarawneh, Zaina Al-Kanaani, Einas Al-Kuwari, Andrew Jeremijenko, Anvar H Kaleeckal, Ali N Latif, Riyazuddin M Shaik, Hanan F Abdul-Rahim, Gheyath K Nasrallah, Mohamed G Al-Kuwari, Adeel A Butt, Hamad E Al-Romaihi, Mohamed H Al-Thani, Abdullatif Al-Khal, Roberto Bertollini, Laith J Abu-Raddad
Journal: New England Journal of Medicine (2023)

Protection against Reinfection with the Omicron BA.2.75 Subvariant To the Editor: The BA.2.75 sublineage of the B.1.1.529(omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may escape neutralizing antibodies.The BA.2.75 sublineage (primarily the BA.2.75.2 subvariant) became the predominant sublineage in Qatar by September 10, 2022 (Section S1 and Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).We estimated the effectiveness of previous infection with SARS-CoV-2 in preventing reinfection with BA.2.75 using a test-negative, case-control study design (Section S2). 1In this study, the effectiveness of previous SARS-CoV-2 infection in preventing reinfection with BA.2.75 was defined as the proportional reduction in susceptibility to infection among persons who had had a previous infection as compared with those who had not been infected.We extracted data regarding SARS-CoV-2 laboratory testing, clinical infection, vaccination, and demographic details from the national SARS-CoV-2 databases, which include the results of all polymerase-chain-reaction and rapid antigen tests conducted at health care facilities in Qatar.Case participants (persons with positive SARS-CoV-2 tests) and controls (persons with negative SARS-CoV-2 tests) were matched exactly according to specific factors in order to balance observed confounders among the study groups (Fig. 1). 1,2Previous infections were classified as pre-omicron infections if the positive test result was obtained before the onset of the omicron wave on December 19, 2021, and as omicron infections if the positive test result was obtained on or after that date. 2 Omicron infections were further classified according to subvariant or sublineage on the basis of the time period during which such infections were predominant: between December 19, 2021, and June 7, 2022, for BA.1 and BA.2 infections 2 ; between June 8, 2022, and September 9, 2022, for BA.4 and BA.5 infections 2 ; and between September 10, 2022, and October 18, 2022, for BA.2.75 infections.Figure S2 shows the process for selecting the study population.Table S1 summarizes the characteristics of the study population, which was found to be broadly representative of the overall population of Qatar (Table S2).Most per-
Case 2-2023: A 76-Year-Old Man with Dizziness and Altered Mental Status
Authors: Antonio Granfone, Brooks P. Applewhite, Biff F. Palmer, Soma Jobbagy
Journal: New England Journal of Medicine (2023)

A 76-year-old man with a history of chronic back pain presented with dizziness and altered mental status. Laboratory evaluation identified anion-gap metabolic acidosis. Additional diagnostic tests were performed.
Substantial Neutralization Escape by SARS-CoV-2 Omicron Variants BQ.1.1 and XBB.1
Authors: Jessica Miller, Nicole P Hachmann, Ai-Ris Y Collier, Ninaad Lasrado, Camille R Mazurek, Robert C Patio, Olivia Powers, Nehalee Surve, James Theiler, Bette Korber, Dan H Barouch
Journal: New England Journal of Medicine (2023)

ed another putative factor directly stimulating testicular testosterone secretion.LH and hCG are structurally similar, and hCG promotes testicular testosterone secretion through stimulation of the LH receptors on the Leydig cells (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org), thus maintaining normal testosterone secretion even in the absence of LH stimulation.Normal adrenal glands on imaging and low LH levels during degarelix treatment ruled out an adrenal or pituitary source in our patient.Germ-cell tumors are the most common source of ectopic hCG production; thus, performing testicular ultrasonography to locate a testicular germ-cell tumor should be the first step in patients with low LH levels and nonsuppressible testosterone during androgen-deprivation therapy.Lung, gastrointestinal, and urothelial cancers should also be considered, because they can produce hCG.High-grade urothelial carcinomas can dedifferentiate into syncytiotrophoblasts that produce hCG. 4,5These patients may present with hematuria, macroorchidism, and gynecomastia, and surgical pathological examination would confirm the presence of syncytiotrophoblasts with positive hCG staining.When clinicians encounter patients whose testosterone levels do not decrease during androgendeprivation therapy and who have low LH levels, consideration of exogenous use of testosterone, adrenal secretion of androgens, or a putative hormone directly stimulating testicular testosterone secretion is warranted.We recommend measuring hCG in such patients.
Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture
Authors: Robert V O'Toole, Deborah M Stein, Nathan N O'Hara, Katherine P Frey, Tara J Taylor, Daniel O Scharfstein, Anthony R Carlini, Kuladeep Sudini, Yasmin Degani, Gerard P Slobogean, Elliott R Haut, William Obremskey, Reza Firoozabadi, Michael J Bosse, Samuel Z Goldhaber, Debra Marvel, Renan C Castillo
Journal: New England Journal of Medicine (2023)

Clinical guidelines recommend low-molecular-weight heparin for thromboprophylaxis in patients with fractures, but trials of its effectiveness as compared with aspirin are lacking.
Growing Evidence and Remaining Questions in Adolescent Transgender Care
Authors: Annelou L.C. de Vries, Sabine E. Hannema
Journal: New England Journal of Medicine (2023)

This week in the Journal, a much-awaited primary report from Chen et al.1 on 2 years of gender-affirming hormones (GAH) in transgender adolescents appears. The approach to adolescent transgender care with early treatment with puberty blockers, and GAH in youth from 16 years of age, originated in the Netherlands ("the Dutch model") and became the dominant medical care model for transgender adolescents.2 Especially over the past decade, marked increases in referrals but limited evidence as to long-term outcomes have led to controversies and debate regarding this approach. Indeed, some European countries are adapting their guidelines and restricting access to care . . .
Psychosocial Functioning in Transgender Youth after 2 Years of Hormones
Authors: Diane Chen, Johnny Berona, Yee-Ming Chan, Diane Ehrensaft, Robert Garofalo, Marco A. Hidalgo, Stephen M. Rosenthal, Amy C. Tishelman, Johanna Olson-Kennedy
Journal: New England Journal of Medicine (2023)

Limited prospective outcome data exist regarding transgender and nonbinary youth receiving gender-affirming hormones (GAH; testosterone or estradiol).We characterized the longitudinal course of psychosocial functioning during the 2 years after GAH initiation in a prospective cohort of transgender and nonbinary youth in the United States. Participants were enrolled in a four-site prospective, observational study of physical and psychosocial outcomes. Participants completed the Transgender Congruence Scale, the Beck Depression Inventory-II, the Revised Children's Manifest Anxiety Scale (Second Edition), and the Positive Affect and Life Satisfaction measures from the NIH (National Institutes of Health) Toolbox Emotion Battery at baseline and at 6, 12, 18, and 24 months after GAH initiation. We used latent growth curve modeling to examine individual trajectories of appearance congruence, depression, anxiety, positive affect, and life satisfaction over a period of 2 years. We also examined how initial levels of and rates of change in appearance congruence correlated with those of each psychosocial outcome.A total of 315 transgender and nonbinary participants 12 to 20 years of age (mean [±SD], 16±1.9) were enrolled in the study. A total of 190 participants (60.3%) were transmasculine (i.e., persons designated female at birth who identify along the masculine spectrum), 185 (58.7%) were non-Latinx or non-Latine White, and 25 (7.9%) had received previous pubertal suppression treatment. During the study period, appearance congruence, positive affect, and life satisfaction increased, and depression and anxiety symptoms decreased. Increases in appearance congruence were associated with concurrent increases in positive affect and life satisfaction and decreases in depression and anxiety symptoms. The most common adverse event was suicidal ideation (in 11 participants [3.5%]); death by suicide occurred in 2 participants.In this 2-year study involving transgender and nonbinary youth, GAH improved appearance congruence and psychosocial functioning. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).
Thromboprophylaxis after Extremity Fracture — Time for Aspirin?
Authors: Matthew Costa
Journal: New England Journal of Medicine (2023)

Hospital-acquired venous thromboembolism remains a common and preventable cause of death, so many health care systems around the world mandate that all patients who are admitted to the hospital undergo a risk assessment for venous thromboembolism.1,2 Patients who have had traumatic injuries are at particular risk for venous thromboembolism as a result of their injuries, the surgeries that are often performed to treat their broken bones, and the patients' relative immobility during recovery.3 Therefore, nearly all patients who undergo surgery for a fracture are considered to be at high risk for venous thromboembolism, and preventative interventions are recommended. Interventions to . . .
Futibatinib for <i>FGFR2</i> -Rearranged Intrahepatic Cholangiocarcinoma
Authors: Lipika Goyal, Funda Meric-Bernstam, Antoine Hollebecque, Juan W. Valle, Chigusa Morizane, Thomas B. Karasic, Thomas A. Abrams, Junji Furuse, Robin K. Kelley, Philippe A. Cassier, Heinz-Josef Klümpen, Heung-Moon Chang, Li-Tzong Chen, Josep Tabernero, Do-Youn Oh, Amit Mahipal, Markus Moehler, Edith P. Mitchell, Yoshito Komatsu, Kunihiro Masuda, Daniel Ahn, Robert S. Epstein, Abdel-Baset Halim, Yao Fu, Tehseen Salimi, Volker Wacheck, Yaohua He, Mei Liu, Karim A. Benhadji, John A. Bridgewater
Journal: New England Journal of Medicine (2023)

Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors.In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes.Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment.In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).
Finding balance in Nigeria's mandatory health insurance
Authors: Yusuf H Wada, Kenneth Okoineme, Omokhudu Idogho, Jennifer Anyanti
Journal: The Lancet Global Health (2023)

The question of sustainable financing for health-service delivery in Nigeria has been at the forefront of health discussions throughout the year.1 This discussion is against the backdrop of an overwhelming gap in health financing in the country,2 and its effect on the quality of Nigerian health-service delivery. The passage of the National Health Insurance Authority bill into law in May, 2022, making health insurance mandatory, and including a vulnerable group fund as one source of financial funding, has brought the question of health financing into sharper focus.
The effects of a peripartum strategy to prevent and treat primary postpartum haemorrhage at health facilities in Niger: a longitudinal, 72-month study
Authors: Anders R Seim, Zeidou Alassoum, Ibrahim Souley, Rachel Bronzan, Aida Mounkaila, Luai A Ahmed
Journal: The Lancet Global Health (2023)

Primary postpartum haemorrhage is the principal cause of birth-related maternal mortality in most settings and has remained persistently high in severely resource-constrained countries. We evaluate the impact of an intervention that aims to halve maternal mortality caused by primary postpartum haemorrhage within 2 years, nationwide in Niger.